Project 2 - Genetic variations linked to the aging hippocampus

项目 2 - 与海马体衰老相关的遗传变异

• 批准号: 9756282
• 负责人: Sandra Barral Rodriguez
• 金额: $ 12.45万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9756282
• 关键词: Aging; Alzheimer' s Disease; Binding Proteins; Bioinformatics; Biophysics; CREB1 gene; CREBBP gene; Cognitive; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Data; Data Set; Dementia; Elderly; Episodic memory; Family; Family Study; Genes; Genetic; Genetic Variation; Genomic Segment; Genomics; Genotype; Hippocampus (Brain); Histone Acetylation; Histones; Human; Impaired cognition; Individual; Life; Link; Memory; Memory Loss; Methods; Molecular; Mus; Mutation; Neurodegenerative Disorders; Outcome; Pathway interactions; Performance; Phenotype; Play; Population; Research; Research Personnel; Response Elements; Role; Sampling; Structural Protein; Study Subject; Targeted Resequencing; Testing; Time; Transcriptional Regulation; Variant; age related; aged; aging brain; aging hippocampus; biophysical analysis; case control; causal variant; cognitive function; cohort; dentate gyrus; differential expression; follow-up; genetic variant; genome wide association study; genome-wide; improved; longitudinal analysis; preservation; prevent; protein structure; segregation; targeted sequencing

PROJECT 2 SUMMARY The main focus of the current proposal is the identification of genetic factors influencing episodic memory function in cognitively healthy elderly by examining a specific set of genes associated with changes in the aging hippocampus. The identification of molecular pathways underlying memory function in cognitively healthy individuals is expected to pinpoint mechanisms for preventing or delaying cognitive decline that might be distinct from those identified by studies of subjects with cognitive impairment or dementia. In a recent study aiming to isolate molecular correlates of the aging human dentate gyrus (DG) and age- related memory loss, investigators of this P50 application identified substantial age-related changes in the human DG expression of 17 genes. Increasing abundance of the gene showing the strongest association (RbAp48) in the DG of aged mice was accompanied by improved memory performance (Pavlopoulos et al. Sci Transl Med. 2013 Aug 28;5(200):200ra115). RbAp48 plays multiples roles in histone acetylation, transcriptional regulation and the cyclic adenosine monophosphate (cAMP) protein kinase A (PKA) cAMP response element binding protein 1 (CREB1) pathway required for normal hippocampal function and aging. In initial analyses we tested whether genetic variants in RbAp48, CREB1 and CREBBP were associated with episodic memory function in large samples of cognitively healthy elderly. Consistent with the idea that this histone pathway is implicated in memory function, we found that cognitively healthy elderly carrying specific variants in these genes showed significantly better average episodic memory function when compared to non-carriers. The overarching aim of this project is to further elucidate the genetic basis of episodic memory function in cognitively healthy individuals by exploring the association of variants in the full list of 17 genes showing age- related expression changes in the DG with episodic memory function, three genes acting in the CREB1 pathway and additional variants in genes outside these pathways in several independent cohorts of cognitively healthy individuals, and to identify the specific genetic variants by targeted resequencing. We aim to follow-up and validate identified mutations by genotyping in several independent cohorts as well as bioinformatics and biophysical analyses assessing the effect of identified mutations on protein structure, level and function.

项目2概要 目前建议的主要焦点是识别影响情景记忆功能的遗传因素 在认知健康的老年人中，通过检查与衰老变化相关的一组特定基因， 海马体。认知健康者记忆功能相关分子通路的鉴定 人们有望找到预防或延缓认知能力下降的机制，这些机制可能是不同的 与认知障碍或痴呆受试者的研究所确定的那些不同。 在最近的一项旨在分离衰老人类齿状回（DG）和年龄的分子相关性的研究中， 相关的记忆丧失，这项P50应用的研究人员发现，在人类中， 17个基因的DG表达。增加显示最强关联的基因（RbAp 48）的丰度， 老年小鼠的DG伴随着改善的记忆表现（Pavlopoulos等，Sci Transl Med. 2013年8月28日;5（200）：200 ra 115）。RbAp 48在组蛋白乙酰化、转录调控中发挥多重作用 环磷酸腺苷（cAMP）蛋白激酶A（PKA）cAMP反应元件结合 蛋白1（CREB 1）通路所需的正常海马功能和老化。在最初的分析中，我们测试了 RbAp 48、CREB 1和CREBBP的遗传变异是否与青少年的情景记忆功能相关？ 认知健康的老年人的大样本。这与该组蛋白途径参与的观点一致 记忆功能，我们发现，认知健康的老年人携带这些基因的特定变体， 与非携带者相比，平均情景记忆功能明显更好。 该项目的总体目标是进一步阐明在成年人中情景记忆功能的遗传基础。 通过探索17个显示年龄的基因的完整列表中的变体之间的关联， 与情节记忆功能相关的DG表达变化，CREB 1通路中的三个基因 在几个独立的认知健康人群中， 个体，并通过靶向重测序鉴定特定的遗传变异。我们的目标是跟进并 通过在几个独立的队列中进行基因分型以及生物信息学来验证所识别的突变， 生物物理分析评估所鉴定的突变对蛋白质结构、水平和功能的影响。